Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:17])[CH:2]=[CH2:3].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])[CH3:19].C(N(CC)CC)C>O1CCCC1>[ClH:30].[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=3)(=[O:29])=[O:28])=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:17])[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ccc(N)cn2)CC1C
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1C
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
305 mg (1.31 mmol) of 6-(4-allyl-3-methylpiperazin-1-yl)pyridin-3-ylamine from Example 13.3 and 301 mg (1.38 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 10 ml of tetrahydrofuran at room temperature, after which 0.55 ml (3.94 mmol) of triethylamine was added dropwise. After that, the reaction mixture was stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and the mixture was made acid with 1N hydrochloric acid and extracted twice with diethylether. The aqueous phase was made alkaline, to pH 9-10, using a 1N aqueous solution of sodium hydroxide and then extracted twice with diethyl ether. After the combined organic phases had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness, the resulting residue was purified by column chromatography (cyclohexane/ethylacetate from 50:50 to 20:80). After that, the filtrate was evaporated down to dryness. The resulting residue was converted into the hydrochloride using ethereal hydrochloric acid, with 417 mg (74% of theory) of the title compound being obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]1[C@H:41]2[C@@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][CH2:34][NH:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[N:6][N:7]2[CH2:16][C:17]([N:33]2[CH2:34][CH2:35][C@H:36]3[C@@H:41]([CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:32]2)=[O:19])=[CH:12][CH:11]=1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)N3CC[C@@H]4CCCC[C@H]4C3)c2c1
Temperature: 25 °C

Procedure:
To a solution of 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 20.9 mg trans-decahydroisoquinoline, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 65-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound. LC-MS: 4.29 min. (m/Z=412.3, 434.3).
Reaction SMILES: [C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([CH:47]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN(C)C(=O)C>[C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:46][CH2:45]5)=[O:43])[N:40]=4)[N:37]=3)[CH:47]=2)=[O:13])[N:10]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CC(C)(C#N)c1nc(C(=O)O)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(=O)c2csc(C(C)(C)C#N)n2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 78.6 %

Procedure:
Using 2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylic acid (104 mg, 0.53 mmol), oxalyl chloride (57 μL, 0.66 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 335, the title compound (179 mg, 78%) was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[H-]>ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 2,4-dinitrobenzoic acid [Aldrich] (1.06 g, 5 mmol) in dichloromethane (20 ml) was treated with oxalyl chloride (2 ml) and 1 drop DMF. Vigorous evolution of gas occurred which ceased after 1 hour. The solution was evaporated to the yellow acid chloride. A solution of phenol (1.5 g, 15.5 mmol) in DMF (20 ml) was introduced into a second flask charged with sodium hydride (480 mg, 60% oil dispersion, 12 mmol). When all the hydride had dissolved this solution was treated with the acid chloride, portionwise over five minutes. The solution was then heated to 60° C. for 12 h, cooled, the solvents removed by evaporation in vacuo, and the residue treated with a solution of 40% sodium hydroxide (50 ml) and ethanol (50 ml). The mixture was stirred at RT for 12 hours then acidified to pH 2 with (2M aq HCl) and extracted into ethyl acetate (3×100 ml). The combined organic phase was washed with saturated brine (50 ml), dried (MgSO4), filtered, and evaporated to a yellow solid. This was purified by flash chromatography (ethyl acetate-hexane) to give 2-nitro-4-phenoxy-benzoic acid (894 mg, 69%);
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[CH2:27]([O:29][C:30](=[O:33])[CH2:31][NH2:32])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]([CH2:31][NH:32][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)=[O:33])[CH3:28]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(NCC(=O)OCC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 57 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.86 g), glycine ethyl ester hydrochloride (0.65 g) and triethylamine (0.47 g) in dichloromethane (15 ml) yielded the title compound, 0.38 g, m.p. 174.5-176° C. (recrystallized from ethanol:water).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[N:10]([N:14]=[N:15][N:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.[Br:17]N1C(=O)CCC1=O.O.C(N(CC)CC)C>C(O)(=O)C>[Br:17][C:11]1[N:10]2[N:14]=[N:15][N:16]=[C:9]2[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:13][CH:12]=1
Reactant: CN1CCN(c2nccn3nnnc23)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(c2ncc(Br)n3nnnc23)CC1
Temperature: 35 °C
Yield: 100 %

Procedure:
8-(4-Methylpiperazin-1-yl)tetrazolo[1,5-a]pyrazine (100 g, 0.456 mol, 1.0 eq.) was suspended in acetic acid (110 ml) under nitrogen and stirred at 35° C. until a solution was obtained. The solution was cooled to 16° C. and N-Bromosuccinimide (82.14 g, 0.461 mol, 1.01 eq.) is added at such a rate that the temperature of the reaction was maintained at 14-18° C. The reaction was monitored and additional aliquots of N-bromosuccinimide added as necessary to ensure conversion was ≧99.5% after 2-3 hours stirring at 20° C. stirring. Water was added, and the solution is cooled to 13° C. The pH of the suspension is adjusted to 8.3-8.5 by addition of triethylamine. The resulting suspension was filtered, washed with water, and dried to afford the desired product (136.02 g, 100% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11]=[O:12].S(=O)(=O)(O)O.C(C1C=CC=CC=1)C>>[C:9]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CCc1ccccc1
Product: O=Cc1cccc2ccccc12
Temperature: 100 °C
Yield: 107.9 %

Procedure:
A bottom-removable four-necked flask having an inner volume of 2 L and equipped with a Dimroth condenser, a thermometer and a stirring blade was charged with 288 g of naphthalene (2.25 mol, produced by Wako Pure Chemical Industries, Ltd.), 821 g of an aqueous 37% by mass formalin solution (10.1 mol as formaldehyde, produced by Mitsubishi Gas Chemical Company, Inc.) and 407 g of 98% by mass sulfuric acid (produced by Mitsubishi Gas Chemical Company, Inc.) in a nitrogen stream, and the content of the flask was reacted while stirring under reflux under ordinary pressure at about 100° C. for 7 hours. Thereto was added 500 g of ethylbenzene (produced by Wako Pure Chemical Industries, Ltd.) as a dilution solvent and left to still stand, and then an aqueous phase as a lower phase was removed. Furthermore, the resultant was subjected to neutralization and washing with water, ethylbenzene and unreacted naphthalene were distilled off under reduced pressure to thereby provide 379 g of a naphthalene formaldehyde resin as a light yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8][CH2:9][CH3:10])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[F:11][C:12]1[CH:19]=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH2:8][CH2:9][CH3:10])[C@@H:2]2[CH3:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CCC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCC[C@]1(O)CCN(c2ccc(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-propylpyrrolidin-3-ol 0.5 oxalate (250 mg), 2,4-difluorobenzonitrile (367 mg) and lithium carbonate (195 mg), the title compound was obtained as colorless oil (yield: 287 mg, yield: 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>[O-]CC.[Na+]>[C:10]([CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(CC#N)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(OC)cc1

Procedure:
Following the procedures outlined in Examples 1 and 3, p-methoxyphenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide solution to give ethyl 3-cyano-3-(p-methoxyphenyl)pyruvate which is then similarly reacted with phenylacetonitrile to yield 2-(p-methoxyphenyl)-5-phenyl-3,4-dioxoadiponitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(NC(C)C)(C)C.C([Li])CCC.[C:23](=[O:25])=[O:24]>>[Cl:1][C:2]1[C:7]([C:23]([OH:25])=[O:24])=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: O=C=O
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CSc1nc(Cl)c(C(=O)O)c(Cl)n1

Procedure:
Methyl iodide can be added to a solution of 2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione and aqueous sodium hydroxide to provide 2-(methylthio)pyrimidine-4,6-diol. The reaction is typically performed in a solvent such as but not limited to ethanol, and may require the use of heat. Addition of phosphorus oxychloride to 2-(methylthio)pyrimidine-4,6-diol will provide 4,6-dichloro-2-(methylthio)pyrimidine. The reaction is typically done at elevated temperature without an additional solvent. 4,6-Dichloro-2-(methylthio)pyrimidine can be added to a mixture of diisopropylamine and n-butyl lithium, followed by the addition of dry carbon dioxide gas to provide 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid. The reaction is typically performed at reduced temperature in a solvent such as but not limited to tetrahydrofuran. A mixture of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid and thionyl chloride can be refluxed together and concentrated, followed by the addition of aqueous ammonia at reduced temperature in a solvent such as but not limited to tetrahydrofuran to provide 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxamide. A compound of formula (1A) wherein B, R2, R3, and m are as described herein, can be reacted with 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxamide in the presence of a base such as but not limited to N,N-diisopropylethylamine to provide compounds of formula (4). The reaction typically requires the use of heat and a solvent such as but not limited to 1,4-dioxane. Compounds of formula (5) can be prepared by reacting compounds of formula (4) with hydrazine hydrate. The reaction is typically performed at ambient temperature in a solvent such as but not limited to 1,4-dioxane. Methyl orthoformate can be reacted with compounds of formula (5) to provide compounds of formula (6). The reaction may require the use of heat. Compounds of formula (7), which are representative of the compounds of Formula (I), can be prepared by reacting compounds of formula (6) with an organozinc compound of formula (2A), wherein Z, A, R1, and n are as described herein and XA is a halide. The reaction typically involves the use of heat and a nickel or palladium catalyst such as but not limited to bis(triphenylphosphine)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) in a solvent such as but not limited to N-methylpyrrolidone, tetrahydrofuran, or mixtures thereof.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:15])=[C:6]([C:10]([CH3:14])=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)([O-:3])=[O:2].B.C1C[O:20][CH2:19][CH2:18]1>C1COCC1>[C:19]([O:9][CH2:7][C:6]1[C:10]([CH3:14])=[CH:11][C:12]([CH3:13])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[CH3:15])(=[O:20])[CH3:18]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1C(=O)O
Reactant: C1CCOC1
Agent: B
Product: CC(=O)OCc1c(C)cc(C)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 3-nitro-2,4,6-trimethylbenzoic acid (6.7 g, 31.9 mmol) in anhydrous THF (100 mL) was added 1 M solution of BH3.THF in THF (63.8 mL, 63.8 mmol) dropwise at 0° C. The reaction mixture was stirred overnight at RT, cooled to 0° C. and quenched with water. The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated to give 1-acetoxymethyl-3-nitro-2,4,6-trimethylbenzene as a light yellow oil (6.3 g, 89%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]([NH:28][C:29]1[C:30](=[O:51])[N:31]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=2)[C@@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:33]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1)[CH3:17].FC(F)(F)C(O)=O.O>C1(C)C=CC=CC=1>[CH3:17][C:16]([NH:28][C@@H:29]1[CH2:33][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:31]([C:40]2[CH:41]=[CH:42][C:43]([O:46][C:47]([F:48])([F:50])[F:49])=[CH:44][CH:45]=2)[C:30]1=[O:51])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=1)[CH3:15]
Reactant: CC(C)(NC1=C[C@H](c2ccccc2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(N[C@@H]1C[C@H](c2ccccc2)N(c2ccc(OC(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Reaction time: 3 h
Yield: 99 %

Procedure:
Add sodium triacetoxyborohydride (98 g, 465 mmol) in two portions to a solution of (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-phenyl-1,5-dihydro-pyrrol-2-one (173 g, 332 mmol) and trifluoroacetic acid (50 mL, 664 mmol) in toluene (1.7 L). Stir for 3 hours and cannulate the mixture into water (2.5 L) over a period of 20 minutes. Extract the water with MTBE (2 L) and wash with water and sodium bicarbonate and concentrate to obtain the title compound as a tan oil (172 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (m, 2H), 7.71 (d, J=8 Hz, 1H), 7.39 (d, J=12 Hz, 2H), 7.21 (m, 8H), 5.16 (m, 1H), 3.42 (m, 1H), 2.68 (m, 1H), 1.63 (m, 1H), 1.38 (s, 3H), 1.43 (s, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:48]=[CH:47][C:17]([CH2:18][N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]3[N:44]=[CH:45][N:46]=[C:20]23)=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:48]=[CH:47][C:17]([CH2:18][N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:3][C:4](=[O:7])[O:5][N:40]=4)=[CH:31][CH:32]=3)=[C:22]([CH2:41][CH2:42][CH3:43])[N:21]3[N:44]=[CH:45][N:46]=[C:20]23)=[CH:16][CH:15]=1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(Cc2ccc(F)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 36%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) drop wise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 minutes. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH4Cl (50 mL) and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 75:25, to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: [O:1]=[C:2]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[CH3:11])[C:3]([OH:5])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[CH:57][CH:56]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N:61]([CH3:62])[C:3](=[O:5])[C:2](=[O:1])[C:6]5[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=5[CH3:11])=[CH:59][CH:60]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nn(C)c(C)c1C(=O)C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)c(C)c1C(=O)C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A mixture of oxo-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acetic acid (134 mg, 0.87 mmol) in dichloromethane (4.0 mL) at 25° C. was treated with triphenylphosphine (145 mg, 0.55 mmol). The reaction was cooled to 0° C. and was treated with N-chlorosuccinimide (74 mg, 0.55 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (290 mg, 0.69 mmol) and triethylamine (0.23 mL, 1.67 mmol). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane and then was washed with a 1N aqueous hydrochloric acid solution (2×50 mL) followed by a saturated aqueous sodium bicarbonate solution (2×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2:98 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford N-{4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-N-methyl-2-oxo-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acetamide (183 mg, 45.8%) as a white solid: (ES)+-HRMS m/e calcd for C32H32N7O4F (M+H)+ 598.2573, found 598.2578.